The pathogenesis of STM is a matter of debate. The most accepted theory is that STM arises from corresponding somatic elements in teratomas, given that in this GCT type, somatic differentiation has already occurred, independently of whether it is originally benign (as in ovarian or prepubertal testicular teratomas) or already malignant (as in postpubertal testicular teratomas) [1, 5]. Coexistence of teratoma and STM in the majority of reported cases supports this hypothesis. Anomalies of chromosome 12, notably duplication of the short arm of chromosome 12 (isochromosome 12p), a hallmark of invasive type II GCT, have been documented in somatic malignancies arising from teratoma, either at the primary site or metastatic location (Fig. 12.1) [6–8], and in gonadal and extragonadal tumors [9]. This finding is also well documented in hematologic malignancies derived from mediastinal GCT [10–14]. Similarly, the classical finding of homozygosity (isodisomy) of mature cystic ovarian teratomas has been demonstrated in somatic adenocarcinomas arising within them [15]. This evidence supports the notion of a metachronous origin of STM from an already neoplastic germ cell. The somatic malignancy thus likely arises from the activation of oncogenes that normally play a role in the development of these tumors at their normal sites. For example, rearrangements of chromosome 2, region 2q34–37, present in rhabdomyosarcomas [16], have been also identified in the rhabdomyosarcoma component of STM [17]. Similarly, genetic alterations in 11q24, which have been frequently reported in Ewing’s sarcoma and PNET, were found in a case of PNET arising from a GCT [17]. Chromosome 5 abnormalities such as del(5q), classically associated with hematologic malignancies, have been identified in leukemias originating from GCT [11, 17]. Finally, loss of heterozygosity reported at 11p13 locus in Wilms’ tumor has been identified in a nephroblastoma arising from testicular GCT [18]. Thus, it appears that the molecular mechanisms associated with neoplastic progression of usual somatic malignancies are also common in those arising from germ cell neoplasia. It is not clear whether the triggers of these mechanisms are the same ones as in regular sites or whether they differ among the different cells of origin and locations of teratomas. Senescence of tissues may explain the development of STM in certain cases, particularly those associated with benign GCT. STM in benign cystic teratomas of the ovary, for example, is more often diagnosed in the fifth to sixth decade of life [19], which contrasts with the usual presentations of these tumors in adolescence and early adulthood, suggesting that a certain elapsing time is necessary for the activation of these oncogenetic mechanisms.

Another mechanism of development of STM-GCT is the overgrowth of immature elements. While the presence of immature tissue elements is relatively common, particularly in type II GCT, an expansile growth of these primitive tissues is associated with more aggressive behavior and metastases from the overgrown component. Examples of primitive tissues that may show overgrowth include neuroepithelium, rhabdomyoblasts, and nephrogenic blastema, and thus, when present, a diagnosis of primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, or nephroblastoma, respectively, is considered. The definition of “overgrowth” is arbitrary and has been traditionally defined in type II testicular tumors as a low-power field (40x) of pure immature elements [1]. However, while this definition appears necessary in type II tumors where immature elements are frequently part of the spectrum of tissues present in these teratomas, the presence of any amount of developmentally immature tissue, in particular neuroepithelium, is considered an adverse finding in ovarian teratomas [20, 21]. Interestingly, the presence of these immature elements, even if extensive, has not been historically considered STM at these sites but rather evidence of “immaturity.” Regardless, the finding is frequently associated with a far more aggressive clinical behavior than the original teratoma.

The occurrence of STM in patients that lacked teratomatous component in their primary or metastatic GCT has prompted other histogenetic theories [17, 22–28]. Some studies have suggested yolk sac tumor (YST) origin as an alternative in these cases [3, 23, 29–31]. Spindle cell sarcomas may arise from sarcomatoid YST by a process of epithelial to mesenchymal metaplasia. Similarly, some intestinal-type adenocarcinomas may arise of progressive differentiation of glandular YST [3]. The development of a high-grade sarcoma component is also a rare complication of spermatocytic tumors, an uncommon scenario where this tumor is associated with malignant clinical behavior (see also Chap. 7) [32]. The mechanism by which these GCT develop a somatic phenotype is unknown but is likely related to the pluripotential nature of germ cells and the activation of differentiation pathways.

The role of chemotherapy in the pathogenesis of STM-GCT, specifically in patients with type II GCT, is not clear. The majority of cases of STM occur in the metastatic and post-chemotherapy setting [3]. However, the extended use of chemotherapy in current management of GCT increases the number of patients with STM who have previously received chemotherapy. Additionally, STM occurs also in patients that did not receive chemotherapy [3, 17, 22, 33]. The presence of STM in metastatic sites without a corresponding counterpart in the primary site has led authors to propose the development of STM from totipotential germ cells at the metastatic site [25, 34]. By destroying the more aggressive tumor components, chemotherapy may select the more indolent slow-growing elements, which after further genetic changes may be responsible for the formation of biologically aggressive STM and late recurrence of GCT [3, 35]. Hematologic malignancies arising from mediastinal GCT were thought to be due to chemotherapy or radiation for a long time. Occurrence of hematologic malignancies in patients that did not receive irradiation or chemotherapy argues against this statement [11, 13, 36]. Further, in contrast to treatment-related leukemia, these GCT-derived somatic-type hematologic malignancies develop earlier [37]. Similarly, STM associated with intracranial GCT was thought to be treatment related. Documented STM in treatment-naïve GCT and the relatively brief interval between initial diagnosis and transformation supports an origin independent of therapy. Despite theories such as partial differentiation of totipotential germ cells with concomitant malignant transformation, tumor arising from differentiated teratomatous elements [23], or dedifferentiation similar to the phenomenon that occurs in liposarcoma and chondrosarcoma [32], the transformation mechanism remains unsettled.

Recognition of a malignant somatic component in GCT depends on the type of malignant component. In general, carcinomatous malignancies are recognized by usual morphologic criteria applied to carcinomas in other locations. Overt cytological atypia, brisk mitotic activity, infiltrative and confluent growth, desmoplastic reaction, and invasive borders are part of such criteria. These criteria are more easily recognizable when the background GCT is benign. However, recognizing these features may prove problematic in the background of a type II GCT, as some elements interpreted as somatic may actually correspond to variants of these GCT, particularly YST. Non-seminomatous GCT usually have a prominent, reactive stroma, which may be confused with desmoplasia. Additionally, the inherent cytologic atypia invariably present in teratomatous elements of type II tumors makes the recognition of a carcinomatous component more difficult [27]. Thus, the addition of a quantitative criterion in carcinomas may be useful to establish a diagnosis of STM in the setting of type II neoplasms [1, 3]. Similarly, because the morphologic features of some sarcomas overlap with normal embryonal or fetal tissue frequently present in teratomas, particularly in type II GCT, it is necessary to establish additional criteria for the diagnosis of a somatic mesenchymal or neuroectodermal malignancy arising in a GCT. As stated above, the most commonly used criterion is the presence of an expansile component exclusively filling at least one low-power microscopic field (40× magnification) [1, 3]. Thus, for example, a nodule composed of embryonal-appearing skeletal muscle would be considered part of a teratoma if it involves less than one low-power field, while it would be considered rhabdomyosarcomatous transformation if the nodule involves a larger area. Even in the setting of high-grade stromal atypia, most authors favor needing a quantitative criterion to diagnose a stromal somatic malignancy [3, 23]. Melanocytic and hematologic neoplasms are usually diagnosed by extrapolating diagnostic criteria applied elsewhere.

The occurrence of STM in pediatric teratomas is well documented. Biskup et al. reported on nine cases of STM associated with pure teratomas (two sacrococcygeal and seven ovarian tumors) [38]; eight of the nine were children and adolescents. Another series reported 14 cases of STM in children and adolescents [39]. While based on the age of the patients and described histology, some of their cases may correspond to type II and type IV tumors; at least some of them were likely type I. STM histologies reported in these series included adenocarcinomas, rhabdomyosarcoma, other sarcomas, neuroendocrine carcinoma, astrocytoma, and neuroblastoma. Sites included ovary, retroperitoneum, sacrococcygeal, and mediastinal. One interesting case of an adenocarcinoma arising in a testicular dermoid cyst in a 52-year-old patient was reported [40]. The patient had had the testicular mass since childhood and developed sudden enlargement of the mass and metastatic disease. The depicted pathology is classical of dermoid cyst and convincingly shows the adenocarcinoma arising from mucinous epithelium within the teratoma. The presence of the mass since childhood, aside from being consistent with a type I neoplasm, underscores the importance of senescence in the development of STM in this setting. A metastasizing PNET has been reported arising in an immature teratoma of a 20-month-old [41]. As stated, STM in type I GCT may occur more frequently than thought, as the occurrence of type I tumors in postpubertal patients has only been recently recognized [42], and reported series do not allow to confidently separate type II from type I teratomas. For example, in a series of GCT associated with sarcomatous STM, three patients with a sarcomatous component had testicular tumors that encompassed exclusively teratomatous elements and thus could have represented type I neoplasms [34]. The overlapping morphology between type I and type IV tumors makes this issue even more likely when dealing with ovarian neoplasms [4].

Spermatocytic tumors (ST) are rare and the presence of an associated sarcomatous component is even rarer. ST is not associated with other GCT and usually has a favorable prognosis (see Chap. 7). In reported cases of ST with a sarcomatous component, undifferentiated spindle cell sarcoma and rhabdomyosarcomas have been mentioned (Fig. 12.6). The presence of a sarcomatous component is associated with poor prognosis and metastatic disease [32, 62, 63].

Published experience with this phenomenon is limited to case reports and small series. The largest one reported five cases of ST with sarcomatous “transformation,” four undifferentiated sarcomas and one rhabdomyosarcoma. Two (possibly three) of the patients died of metastatic disease [32]. Another series reported two cases of ST with sarcomatous component. The sarcomatous element in one case was rhabdomyosarcoma, while the other case had primitive mesenchymal spindle cell sarcoma. Both cases were older than 40 years; their sarcomatous component metastasized and had a poor outcome despite aggressive treatment. In their description of the ST component, the authors point out slight differences with classic description, including high mitotic rate and atypical mitotic figures [64]. One case report presented an ST with undifferentiated sarcomatous component in a 43-year-old male. The tumor was resected but chemotherapy was not given. The patient developed a recurrent scrotal mass and multiple bilateral lung metastases 9 months later. A chemotherapy regimen of cisplatin, bleomycin, and etoposide was initiated, but the patient died after 1 month [65]. Similarly, another case report presented an ST in a 51-year-old male with rhabdomyosarcoma component, metastasis to the lungs, liver and retroperitoneal lymph nodes, and death 2 months after the diagnosis [62].

The exact mechanism explaining the origin of sarcomatous component is not clear. As expected, teratomatous elements were absent in all reported cases. True et al. suggested that the sarcomatous components are an expression of anaplastic transformation of the ST [32]. One could also theorize that the sarcomatous component is a result of the pluripotential features of the neoplastic germ cell, although it is not clear why only mesenchymal neoplasms arise in this setting. Due to aggressive behavior of ST with sarcomatous component, additional treatment is warranted, although no specific modality is favored based on the limited experience. These tumors are rare and the effectiveness of chemotherapy and/or radiotherapy is not clear [66, 67].

Mature cystic teratomas of the ovary (type IV GCT) can also be complicated by STM, and this phenomenon is extensively reviewed in Chap. 6. A few salient aspects will be discussed here.

STM occurs in 1.5–3 % of mature cystic teratomas [19, 68]. Contrary to what occurs in type II GCT, the majority of STM arising in mature cystic teratomas of the ovary are squamous cell carcinomas (Fig. 12.7) [69]. They seem to affect elderly women in their fifth and sixth decade [19]. Other epithelial neoplasms that may be found within mature cystic teratomas include adenocarcinoma (Fig. 12.8) [70], neuroendocrine carcinoma, and transitional cell carcinoma [71]. Sarcomas are much less frequent and include osteosarcoma [71, 72], rhabdomyosarcoma, angiosarcoma (Fig. 12.9), malignant fibrous histiocytoma, chondrosarcoma, spindle cell sarcoma, and undifferentiated sarcoma [73, 74]. Malignant melanomas are much less common than metastatic melanomas to the ovary [75, 76]. A thorough list of histologies reported in STM in mature cystic ovarian teratomas is presented in Chap. 6 in Table 6.​5.